1. Field of the Invention
The present invention relates to novel tripeptide derivatives containing a pyroglutamic acid residue and more particularly, to tripeptide derivatives containing a pyroglutamic acid residue which possess a protease inhibitory activity, or pharmaceutically acceptable salts thereof. The invention also relates to protease inhibitors comprising the same as an effective ingredient.
2. Related Art Statement
It is well known that a variety of proteases are present in vivo. There are known trypsin-like enzymes, for example, plasmin, trypsin, kallikrein, thrombin, urokinase, etc., or chymotrypsin-like enzymes, pepsin-like enzymes, or the like. It is known that these proteases cause various diseases when they are abnormally activated by some reason.
Accordingly, a substance having an inhibitory activity against these proteases is useful as a certain therapeutic agent in the clinical field. For example, an anti-plasmin agent is useful as a hemostatic, anti-inflammatory agent or anti-allergic agent; an anti-thrombin agent is useful for the treatment of thrombosis; an anti-trypsin agent is useful for the treatment of pancreatitis; an anti-kallikrein agent is useful for the treatment of inflammation and ulcer; and an anti-urokinase agent is useful for preventing hemorrhagic conditions in thrombolytic therapy with urokinase.
Protease inhibitors having such activities have been heretofore developed but they have merely poor protease inhibitory activities and are insufficient to provide as drugs for practical use. Protease inhibitors having a sufficient inhibitory activity against a plurality of proteases has not been yet developed, either.
For example, certain tripeptide derivatives containing an argininal group are widely known. That is, acetyl-L-leucyl-L-leucyl-L-argininal (leupeptin) is one of the argininal-containing tripeptide derivatives produced by a certain kind of microorganism (cf., e.g., J. Antibiotics (Tokyo), 1969, 22, 283) but its inhibitory activity is poor (cf., e.g., Taisha, 1977, 14, 1087). D-Phenylalanyl-L-propyl-L-argininal is known to be a thrombin inhibitor (see, e.g., Symposia Biologica Hungarica, 1984, 25, 277) but its inhibitory activity against other similar trypsin-like enzymes is weak. Umezawa et al. synthesized many derivatives of leupeptin but any of them merely shows a weak inhibitory activity against trypsin-like enzymes (cf., J. Antibiotics (Tokyo), 1988, 41 (2), 220).